Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
J Crohns Colitis. 2022 May 11;16(Supplement_2):ii3-ii19. doi: 10.1093/ecco-jcc/jjac034.
The interleukin-23 [IL-23] cytokine, derived predominantly from macrophages and dendritic cells in response to microbial stimulation, has emerged as a critical promoter of chronic intestinal inflammation. Genome-wide association studies linking variants in IL23R to disease protection, bolstered by experimental evidence from colitis models, and the successful application of therapies against the IL-12/IL-23 shared p40 subunit in the treatment of inflammatory bowel disease [IBD] all provide compelling evidence of a crucial role for IL-23 in disease pathogenesis. Moreover, targeting the p19 subunit specific for IL-23 has shown considerable promise in recent phase 2 studies in IBD. The relative importance of the diverse immunological pathways downstream of IL-23 in propagating mucosal inflammation in the gut, however, remains contentious. Here we review current understanding of IL-23 biology and explore its pleiotropic effects on T cells, and innate lymphoid, myeloid and intestinal epithelial cells in the context of the pathogenesis of IBD. We furthermore discuss these pathways in the light of recent evidence from clinical trials and indicate emerging targets amenable to therapeutic intervention and translation into clinical practice.
白细胞介素-23 [IL-23] 细胞因子主要由巨噬细胞和树突状细胞在微生物刺激下产生，已成为慢性肠道炎症的关键促进因素。全基因组关联研究将 IL23R 中的变体与疾病保护联系起来，结肠炎模型的实验证据和针对 IL-12/IL-23 共享 p40 亚基的治疗方法在炎症性肠病 [IBD] 的成功应用都提供了强有力的证据表明 IL-23 在疾病发病机制中起着至关重要的作用。此外，针对 IL-23 特异性 p19 亚基的靶向治疗在最近的 IBD 二期研究中显示出了巨大的希望。然而，IL-23 下游的多种免疫途径在肠道黏膜炎症中的相对重要性仍存在争议。本文综述了目前对 IL-23 生物学的认识，并探讨了其在 IBD 发病机制中对 T 细胞以及固有淋巴样细胞、髓样细胞和肠道上皮细胞的多效作用。我们还根据临床试验的最新证据讨论了这些途径，并指出了可进行治疗干预和转化为临床实践的新兴靶点。
